Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B cell activation.

Abstract Background AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival. Objective We investigated the mechanisms underlying recurrent sino-pulmonary infections and hypogammaglobulinemia in 15 patients, ranging from three to 34 years of age, from nine kindreds. Only two patients, both of whom had mildly impaired T cell proliferation, each had a single clinically significant opportunistic infection. Methods Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function. Results We identified two different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but one patient have intact hearing. The patients’ B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients’ B cells exhibit defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize non-mitochondrial metabolism, these findings reveal a less strict cellular dependence of T cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function. Conclusions Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B cell activation and antibody production.